KR0164464B1 - A process for preparing penicillanic acid derivatives - Google Patents

Abstract

The present invention is used as an antimicrobial agent, an antimicrobial inhibitor, or an intermediate thereof, consisting of reacting a compound of formula (I) and samarium (II) iodine at 0 to -78 ° C in a tetrahydrofuran and acetonitrile solvent. It relates to a process for preparing the general formula (II) compound.

Wherein X 'and X are each an elemental halogen or hydrogen, except that X is a halogen element or hydrogen or where both X' and X are hydrogen; n is 0, 1 or 2; R is hydrogen, an alkali metal cation, a carboxylate forming group or a carboxy protecting group.

Description

Preparation method of peniclanic acid derivative

The present invention relates to a novel process for synthesizing a compound of formula (II) having one or two halogens at the 6 position, which consists in dehalogenating a penicsilane acid derivative of formula (I).

Wherein X 'and X are each a halogen element or a hydrogen or X' and X are both hydrogen; n is 0, 1 or 2; R is hydrogen, an alkali metal cation, a carboxylate forming group or a carboxy protecting group.

The general formula (II) compounds are useful as intermediates for the preparation of inhibitors of antimicrobial agents or inhibitors of antimicrobial degrading enzymes, and are useful as intermediates for the preparation of antimicrobial agents.

In the above general formula (II) compounds, peniclanic acid 1,1-dioxide of X = H, n = 2 is known to be useful for enhancing antimicrobial activity in combination with antibacterial and beta-lactam antibiotics.

In addition, other penicilanic acid derivatives represented by formula (II) are useful as intermediates for the preparation of other antimicrobial agents or inhibitors of antimicrobial degrading enzymes.

Resistant bacteria that are particularly resistant to beta-lactam antibiotics, such as penicillin and cephalosporin, are known to inactivate the drug by hydrolyzing the beta-lactam antibiotic beta-lactam structure in most cases by secreting an enzyme called beta-lactamase.

Substances that have the ability to inhibit beta-lactamase activity are called beta-lactamase inhibitors (inhibitors). When these inhibitors are used in combination with antibiotics such as penicillin, they are more antibacterial than the sum of the antimicrobial effects of the individual inhibitors and antibiotics It is said that there is an improvement in antibacterial effect that the effect is better.

The compound represented by the general formula (II) and salts thereof are known substances (Antimicrob. Agents Chemother, 21, 506 (1978)), useful as inhibitors of beta lactamase, and beta to resistant bacteria that secrete beta lactamase. It is known to enhance the effects of lactam antibiotics.

The following method is known as a method of preparing general formula (II) compound by the dehalogenation method. In US Pat. No. 4,180,506, mono-bromophenicillin sulfonic acid was synthesized from 6,6-penicillin sulfonic acid by hydrogenation using a palladium / carbon catalyst, but this method has the disadvantage of using high pressure hydrogen, EP 0013617 and Tetrahedron 15, 2477 (1983) obtained 6-bromine isomers from 6,6-dibromophenicillinsulfonic acid and ester derivatives thereof using trialkyl and triallyl tin hydrides, but the reaction was carried out at high temperature (about 100 ° C.). It must proceed while refluxing, and since a mixture of the starting material and the 6α-, 6β-monobromophenicillin sulfonic acid compound is obtained, there is a difficulty in separation. EP 0092286 and EP 139282 debrominated 6,6-dibromo penicillin sulfonic acid and its ester derivatives with zinc and magnesium, respectively, but the reaction conditions should always be maintained at an acid with a pII of 2-6. WO 87/06230 describes debromination with alkyl phosphites. This method has a long reaction time of 2 to 4 hours and has the disadvantage of toxic phosphite.

The present invention relates to a process for preparing a compound of formula (II) comprising the use of samarium (II) iodine and a compound of formula (1) in a tetrahydrofuran or acetonitrile solvent.

Wherein X 'and X are each a halogen element or a hydrogen or X' and X are both hydrogen; n is 0, 1 or 2; R is hydrogen, an alkali ion cation, a carboxylate forming group or a carboxy protecting group. Elements or groups that can be used as the alkali metal cation, carboxylate group or carboxy protecting group represented by R are well known in the art, for example, alkali metal cations such as sodium, potassium, magnesium, 4-methoxybenzyl , 4-nitrobenzyl, diphenylmethyl, allyl, tert-butyl, alkyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, trichloroethyl, trimethylsilyl and the like can be used, but is not limited thereto.

Samarium is a lanthanide element, and samarium (II) iodine can be obtained by treating samarium metal with diiodine methane, diiodine ethane, iodine or mercury (II) iodine in a tetrahydrofuran or acetonitrile solvent. In general, it is quantitatively prepared by stirring samarium and diiodine methane or diiodine ethane at room temperature for 1 to 2 hours in a tetrahydrofuran or acetonitrile solvent.

J. Org, Chem., 51, 1135 (1986); J. Org. Chem, 51, 2596 (1986), Tetrahedron Lett., 28, 4437 (1987) describe the dehalogenation of the α-position of ketone compounds using samarium (II) iodine.

The production method of the present invention is carried out at room temperature to -78 ℃. The higher the reaction temperature, the faster the reaction, but considering the reaction yield and the purity of the reaction product is preferably -60 ℃ to -78 ℃. Since the preparation method of the present invention can be carried out under neutral, acidic or basic conditions, the liquidity of the reactant itself used is sufficient.

Tetrahydrofuran or acetonitrile may be used as the reaction solvent.

Samarium (II) iodine may be used in a molar ratio of 2.0 to 4.0 times with respect to the general formula (I) compound, but it is preferable to use about 2.5 to 3.8 times.

The addition of hexamethylphosphoramide is preferable in terms of yield and reaction rate, and the amount of use is preferably 0% to 20% with respect to the solvent, but preferably 5% to 10%.

The extra samarium (II) iodine can be decomposed by adding saturated ammonia water, and the reaction mixture is extracted with an organic solvent and evaporated to dryness to obtain a compound of formula (II).

In the present invention using samarium (II) iodine, the reaction is completed within a few minutes at low temperature, and the target compound can be obtained quantitatively with high purity, and the reaction is clean, safe and easy to separate. In addition, when the general formula (I) compound as the starting material is a dihalogen compound, only the mono α-halogen compound, which is a stereoisomer, can be obtained purely or a penicilanic acid derivative in which all halogens are removed by controlling the reaction time. There is an advantage. Mono α-halogen compounds can be used as intermediates for preparing inhibitors of other antimicrobial degrading enzymes.

The following examples will illustrate the method of the present invention in more detail, but the scope of the present invention is not limited by the examples.

Nuclear magnetic resonance spectra (300MIIz) use the following abbreviations, depending on the shape of the peak; s: single line, d: double line, t: triplet, q: quadruple

Example 1

Preparation of 6α-bromo peniclanic acid diphenylmethyl ester 1,1-dioxide

A:

In a nitrogen atmosphere, 200 mg (0.36 mmol) of 6,6-dibromo peniclanic acid diphenylmethyl ester 1,1-dioxide was dissolved in 5 ml of tetrahydrofuran and cooled to -78 ° C, followed by hexamethylphosphoramide (8.6 v). / v%) containing 5.5 ml (0.90 mmol) of samarium diiodine (0.16 M) solution was slowly added to react for 10 minutes. Saturated ammonia water was added to the reaction vessel, 20 ml of ethanol was added thereto, and the mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 170 mg (0.36 mmol, 100%) of the title compound.

B:

In a nitrogen atmosphere, 20 mg (0.36 mmol) of 6,6-dibromo peniclanic acid diphenylmethyl ester 1,1-dioxide was dissolved in 5 ml of tetrahydrofuran, and 5.5 ml (0,80 mmol) of samarium diiodine solution was added at room temperature. When added slowly, the reaction was completed within about 5 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 162 ml (0.36 mmol, 95%) of the title compound.

Example 2

Preparation of 6α-dibromo peniclanic acid diphenylmethyl ester

A:

In a nitrogen atmosphere, 200 mg (0.38 mmol) of 6,6-dibromo peniclanic acid diphenylmethyl ester was dissolved in 5 ml of tetrahydrofuran and cooled to -78 ° C, followed by hexamethylphosphoramide (8.6 v / v%). After slowly adding 7.5 ml (1.23 mmol) of samarium diiodine (0.16 M) solution, the reaction was completed within about 10 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 169 mg (0.38 mmol, 100%) of the title compound.

B:

Under nitrogen atmosphere, 200 mg (0.38 mmol) of 6,6-dibromo peniclanic acid diphenylmethyl ester was dissolved in 5 ml of tetrahydrofuran, cooled to 0 ° C., and then slowly added to samarium diiodine solution (1.87 mmol) for about 10 minutes. The reaction was complete within a while. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 160 mg (0.36 mmol, 95%) of the title compound.

Example 3

Preparation of 6α-Bromophenic Acid Diphenylmethyl Ester 1-oxide

A:

In a nitrogen atmosphere, 200 mg (0.37 mmol) of 6,6-dibromo peniclanic acid diphenylmethyl ester 1-oxide was dissolved in 3 ml of tetrahydrofuran, cooled to -78 ° C, and then hexamethylphosphoramide (8.6 v / 7.5 ml (1.23 mmol) of samarium diiodine (0.16 M) solution containing v%) was slowly added to react for 10 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 150 mg (0.33 mmol, 88%) of the title compound.

B:

In a nitrogen atmosphere, 200 mg (0.37 mmol) of 6,6-dibromo peniclanic acid diphenylmethyl ester 1-oxide was dissolved in 3 ml of tetrahydrofuran, and a samarium diiodine (0.16 M) solution (1.87 mmol) was slowly added at room temperature. The reaction was added for 10 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 137 mg (0.30 mmol, 80%) of the title compound.

Example 4

Preparation of 6α-iodo peniclanic acid diphenylmethyl ester 1,1-dioxide

Except for using 236 mg (0.36 mmol) of 6,6-diiodophenylanic acid diphenylmethyl ester 1,1-dioxide, the target compound was obtained in 97% yield.

Example 5

Preparation of 6α-iodo Peniclanic Acid Diphenylmethyl Ester

A target compound was obtained in a yield of 98% by the same method as Example 2A, except that 237 mg (0.38 mmol) of 6,6-diiodophenylanic acid diphenylmethyl ester was used.

Example 6

Preparation of 6α-iodo peniclanic acid diphenylmethyl ester 1-oxide

A target compound was obtained in a yield of 99% by the same method as Example 3A, except that 236 mg (0.37 mmol) of 6,6-diiodophenylanic acid diphenylmethyl ester 1-oxide was used.

Example 7

Preparation of Peniclanic Acid Diphenylmethyl Ester 1,1-Dioxide

In a nitrogen atmosphere, 150 mg (0.31 mmol) of 6α-bromo (or -iodine, -chloro) peniclanic acid diphenylmethyl ester 1,1-dioxide was dissolved in 4 ml of tetrahydrofuran, cooled to -78 ° C, and then hexamethylphosphate. 4.0 ml (0.65 mmol) of samarium diiodine (0.16 M) solution containing poramide (8.6 v / v%) was slowly added to react for 10 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 105 mg (0.29 mmol, 92%) of the title compound.

Example 8

Peniclanic Acid Diphenylmethyl Ester Preparation

In a nitrogen atmosphere, 150 mg (0.34 mmol) of 6-bromo (or iodine, chloro-) peniclanic acid diphenylmethyl ester was dissolved in 5 ml of tetrahydrofuran and cooled to -78 ° C, followed by hexamethylphosphoramide (8.6 v / v). 5.2 ml (0.85 mmol) of samarium diiodine (0.16 M) solution containing%) was slowly added to react for 10 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 113 mg (0.31 mmol, 90%) of the title compound.

Example 9

Peniclanic Acid Diphenylmethyl Ester 1-oxide Preparation

In a nitrogen atmosphere, 150 mg (0.33 mmol) of 6-bromo (or iodine, chloro-) peniclanic acid diphenylmethyl ester 1-oxide was dissolved in 5 ml of tetrahydrofuran and cooled to -78 ° C, followed by hexamethylphosphoramide ( 5.2 ml (0.85 mmol) of samarium diiodine (0.16 M) solution containing 8.6 v / v%) was added slowly and reacted for 10 minutes. Saturated ammonia water was added to the reaction vessel, and 20 ml of ethyl acetate was added thereto and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 113 mg (0.30 mmol, 90%) of the title compound.

Claims (4)

A process for preparing the compound of formula (II) comprising the reaction of a compound of formula (I) with samarium (II) iodine at 0-78 ° C. in a tetrahydrofuran or acetonitrile solvent Wherein X 'and X are each a halogen element or a hydrogen or X' and X are both hydrogen; n is 0, 1 or 2; R is hydrogen, an alkali metal cation, a carboxylate forming group or a carboxy protecting group. The method of claim 1, further wherein hexamethylphosphoramide is added at 20% or less by weight relative to the solvent. The method according to claim 1, wherein the compound of formula (I) and samarium (II) iodine are reacted in a molar ratio of 1: 2 to 1: 4. The method according to claim 1, wherein the compound of formula (I) is reacted with samarium (II) iodine, followed by further addition of saturated ammonia water to decompose the extra samarium (II) iodine.